Previously we have studied the contribution of histone modifications, DNA methylation and their regulatory enzymes to transcriptional regulation in a variety of cellular systems. Recent studies have suggested cellular heterogeneity in gene expression even in the same cell population. The question is whether there is a similar heterogeneity in chromatin states in the apparently same cells. To address this question, we have developed the single-cell DNase-seq technique that can be used to detect chromatin states in single-cells or small number of primary cells. By applying this technique to NIH3T3 and mouse ES cells, we show the the heterogeneity of chromatin accessibility underlies the heterogeneity of gene expression across different cells. We also demonstrated its application in identifying potential functional mutations in human cancers. To develop more technologies that can be used to analyze the mammalian epigenomes, we developed 3e Hi-C for analyzing the three dimensional organization in the nucleus (Ren et al., Mol Cell 2017). To characterize genome-wide enhancer-promoter interactions at high resolution, we developed a novel technique, Transposition-mediated Analysis of Chromatin Looping (Trac-looping) (Nature Methods, in press). To analyze the epigenome at a single-cell level, in addition to the previous single-cell DNase-seq assay (Nature 2015), we have developed a single-cell MNase-seq for analysis of genome-wide nucleosome positions (Nature 2018). Application of scMNase-seq to NIH3T3 cells, mouse primary naive CD4 T cells and mouse embryonic stem cells reveals two principles of nucleosome organization: first, nucleosomes in heterochromatin regions, or that surround the transcription start sites of silent genes, show large variation in positioning across different cells but are highly uniformly spaced along the nucleosome array; and second, nucleosomes that surround the transcription start sites of active genes and DNase I hypersensitive sites show little variation in positioning across different cells but are relatively heterogeneously spaced along the nucleosome array. We found a bimodal distribution of nucleosome spacing at DNase I hypersensitive sites, which corresponds to inaccessible and accessible states and is associated with nucleosome variation and variation in accessibility across cells. Nucleosome variation is smaller within single cells than across cells, and smaller within the same cell type than across cell types. A large fraction of naive CD4 T cells and mouse embryonic stem cells shows depleted nucleosome occupancy at the de novo enhancers detected in their respective differentiated lineages, revealing the existence of cells primed for differentiation to specific lineages in undifferentiated cell populations. Furthermore, we have developed single-cell ChIC-seq and ACT-seq for the analysis of histone modifications at a single-cell level.